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Design of optimized epigenetic regulators for durable gene silencing with application to PCSK9 in nonhuman primates by Shaoshuai Mao & Wenbo Peng & Zhengyan Feng & Yang Chen & Jing Sun & Haiting Chen & Pengcheng Wang & Pinzheng Huang & Junzheng Zhao & Leilei Wu & Yifan Wang & Junjian Liu & Hao Luo & Ying Zang & Changqing Yang & Xue Qiao & Zhiwei Lu & Hongjun Wu &... is a book available to read on EtoBox.

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Nature Biotechnology, doi:10.1038/s41587-025-02838-yEpigenetic editing is a promising strategy for modifying gene expression while avoiding the permanent alterations and potential genotoxicity of genome-editing technologies. Here we designed optimized epigenetic regulators (EpiRegs) by testing combinations of transcription activator-like efector (TALE)-based and catalytically deactivated Cas9 (dCas9)-based epigenetic modifcation efectors and fusion protein structures. TALE-based EpiReg (EpiReg-T) achieved a fnal efciency of 98% in mice, surpassing the initial dCas9-based efciency of 64%. We demonstrated the approach in macaques by introducing DNA methylation and histone modifcations to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, thereby lowering low-density lipoprotein cholesterol levels. A single dose of EpiReg-T delivered with lipid nanoparticles achieved efcient (>90%) and long-lasting (343 days) silencing of PCSK9 in the liver. Integrative multiomic analyses revealed minimal of-target efects in EpiReg-T-treated monkeys, mice and human-derived cells. EpiReg can be redirected to other genes by reengineering the DNA-binding domain. Our fndings represe

Author

Shaoshuai Mao & Wenbo Peng & Zhengyan Feng & Yang Chen & Jing Sun & Haiting Chen & Pengcheng Wang & Pinzheng Huang & Junzheng Zhao & Leilei Wu & Yifan Wang & Junjian Liu & Hao Luo & Ying Zang & Changqing Yang & Xue Qiao & Zhiwei Lu & Hongjun Wu &...

Publisher

x

Published

2025

Language

EN